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Abstract:

Medical devices to treat stenosis, inhibiting restenosis, plaque removal,
crossing totally occluded arteries or veins, treatment of vulnerable
plaque, as well as removal of blood clots from the patient body arc
disclosed. Such devices maybe used alone or in combination with
therapeutic drugs. In some embodiments, flow protection devices are used
for homogeneous drug delivery and removal from the patient to minimize
the systemic effect. In some other embodiments, ablated tissue or blood
clots are removed from the body after the procedure.

Claims:

1. A medical device for treating endovascular disease, comprising: an
elongated ultrasound transmission member having a distal end, and a
proximal end connectable to a separate ultrasound generating device and
configured to propagate ultrasound energy to the distal end of the
ultrasound transmission member; and a catheter partially surrounding the
ultrasound transmission member and aligned to deliver ultrasound surface
waves to a treatment area adjacent to the distal end of the ultrasound
transmission member.

2. The device of claim 1, wherein a radiopaque marker is attached to the
distal end of the ultrasound transmission member.

3. The device of claim 1, wherein an anchor member is attached to the
distal end of the ultrasound transmission member.

4. The device of claim 3, further including a polymer sheath positioned
along the ultrasound transmission member and the anchor member.

5. The device of claim 4, wherein a polymer shell is positioned around
the distal end of the ultrasound transmission member and is at least
partially surrounding the radiopaque marker, the anchor member and the
ultrasound transmission member.

6. The device of claim 1, wherein a separate tip is attached on the
distal end of the ultrasound transmission member.

7. The device of claim 6, wherein an anchor member is attached to the
separate tip.

8. The device of claim 7, further including a radiopaque marker
positioned on the ultrasound transmission member.

9. The catheter of claim 8, wherein a polymer shell is at least partially
surrounding the ultrasound transmission member.

10. The device of claim 9, further including a polymer sheath positioned
along the ultrasound transmission member.

11. The device of claim 1, wherein a radiopaque marker is attached to the
distal end of the catheter.

12. The device of claim 1, wherein the catheter includes a guidewire
lumen.

13. The device of claim 1, wherein the catheter can be repositioned along
the ultrasound. transmission member.

14. The device of claim 1, wherein the medical device operates at
frequencies between 1 kHz and 10 MHz, and delivers less than 20 Watts of
ultrasound energy.

15. The device of claim 1, wherein the ultrasound surface waves are
delivered in one of the following mode of operation: continuous, pulse,
modulated mode or a combination thereof.

16. The device of claim 1, wherein the surface waves propagate from the
ultrasound transmission member to the treatment area through contact with
the treatment area.

17. The device of claim I, further including delivery of irrigant along
the ultrasound transmission member.

18. The device of claim 17, wherein surface waves propagate from the
ultrasound transmission member to the treatment area through the
surrounding irrigant.

19. The device of claim 18, wherein a surrounding irrigant is in mixture
with blood.

21. The medical device of claim 1, wherein the ultrasound transmission
member is connected at its proximal end to a sonic connector, wherein the
ultrasound transmission member is surrounded by absorbers positioned
around the proximal end of the ultrasound transmission member and
positioned outside an area of one-quarter wavelength from the sonic
connector.

22. A medical device for treating endovascular disease, comprising an
elongated ultrasound member configured to generate surface waves to
modify cell structure in a treatment area to increase endovascular drug
uptake.

Description:

[0001] This application claims priority to U.S. Provisional Application
No. 61/278,353, of Wallace, filed on Oct. 6, 2009, and is also a
continuation-in-part of co-pending application Ser. No. 13/438,221 filled
on Apr. 3, 2012, which is a continuation-in-part of co-pending
application Ser. No. 13/134,470 filled on Jun. 8, 2011, which is a
continuation-in-part of co-pending application Ser. No. 12/930,415 filed
Jan. 6, 2011, which is a continuation-in-part of co-pending application
Ser. No. 12/925,495 filed Oct. 22, 2010, which is a continuation-in-part
of co-pending application Ser. No. 12/807,129, filed Aug. 27, 2010, which
is in turn continuation-in-part of co-pending application Ser. No.
12/661,853, filed Mar. 25, 2010.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention is related to medical devices and methods.
More specifically invention is related to endovascular devices and
methods for the treatment of stenosis, inhibiting restenosis, plaque
removal, thrombus removal, crossing totally occluded arteries or veins,
the treatment of vulnerable plaque and the removal of blood clots from
the other areas in the human body. Treatment of these diseases may be
performed with or without the use of therapeutic drugs.

BACKGROUND

[0003] Atherosclerosis and its consequences, including arterial stenosis,
venous stenosis and hypertension, represent a major health problem both
in the U.S. and throughout the world. A common treatment for arterial
stenosis and occlusions involves balloon angioplasty, more specifically
percutaneous transluminal balloon angioplasty (PTA), a procedure in which
a balloon catheter is advanced through the artery to the stenotic or
occluded site and expanded there to widen the artery. A stent is also
commonly placed at the stenotic site for the purpose of maintaining
patency of the newly opened artery. Angioplasty and stent implantation,
however, often are of limited long term effectiveness due to restenosis
and reocclusion. In a study of intracoronary stenting, for example,
restenosis was observed to occur over the long term in 15% to 30% of
patients (Serruys et al., 1994, N. Engl. J. Med., 331:489).

[0004] The use of therapeutic agents with presumed antistenotic or
anti-intimal thickening activity has been combined with stent-based
therapy. Drug-eluting stents that deliver a drug such as Sirolimus or
Paclitaxel have been used most frequently in the hope that a slowly
eluting drug will impede restenosis. In another recent approach, balloon
catheters with drug eluting balloons have been tried for restenosis
prevention. While these approaches have met with some success, the
restenosis problem is far from solved, as drug eluting stents and
balloons have had mixed results in clinical studies.

[0005] Yet another approach to treating vascular stenosis and preventing
restenosis involves administering a therapeutic agent at the stenosis
site, either alone or in conjunction with a conventional endovascular
interventional procedure such as angioplasty or venoplasty, with or
without stenting. In this approach a therapeutic agent is delivered to
the stenotic site through a catheter. Numerous therapeutic agents have
been examined for their anti-proliferative effects, and some of which
have shown some effectiveness with regard to reducing intimal
hyperplasia. These agents, by way of example, include heparin and heparin
fragments, angiotensin converting enzyme (ACE) inhibitors, angiopeptin,
cyclosporin A, goat-anti-rabbit PDGF antibody, terbinafine, trapidil,
tranilast, interferon-gamma, rapamycin, corticosteroids, fusion toxins,
antisense oligonucleotides, and gene vectors. Other non-chemical
approaches have also been tried, such as ionizing radiation.

[0006] While holding considerable promise, the methods and devices for
delivering antistenotic therapeutic agents to blood vessel wall tissue
are as yet not fully satisfactory. Absorption of the therapeutic agent
into the blood vessel wall, for example, represents a significant
challenge. Furthermore, it would be advantageous to incorporate or
coordinate delivery of a therapeutic with an angioplasty, venoplasty
and/or stent placement procedure. Any attractive new methods or devices
for therapeutic agent delivery would need to be safe, effective, and
relatively simple to perform. At least some of these objectives are met
by the embodiments of the invention as provided herein.

[0007] A need exists for devices and methods that allow ultrasound energy
to be more evenly applied to the vessel wall, and to induce homogeneous
cellular changes to increase vessel permeability, so that therapeutic
drugs can be more effective. Ideally, such devices would provide
sufficient delivery of ultrasound energy to the surrounding tissue
(either to small or large vessels), and consequently increase vessel drug
uptake. While such devices should provide necessary ultrasound energy,
they also should avoid and prevent vascular injures. Also, dissolving
endovascular blood clots maybe more efficient when ultrasound energy is
delivered uniformly to the treatment area. At least some of these
objectives will be met by the present invention.

BRIEF SUMMARY OF THE INVENTION

[0008] The scope of the present invention is best defined by the appended
claims. In certain instances, detailed descriptions of ultrasound
physics, well-known devices, compositions, components, mechanisms and
methods are omitted so as to not obscure the description of the present
invention with unnecessary details.

[0009] The inventive technology described herein provides new methods and
devices to improve the treatment of vascular stenosis and re-stenosis
using ultrasound technology to enhance delivery of therapeutic agents
directly to a targeted therapeutic site, such as a stenotic site on an
arterial or vein wall. Aspects of the anti-stenotic treatment methodology
may include ultrasound-enhanced delivery of therapeutic agents to a
stenotic site to reduce plaque and to increase the patency of the
afflicted vessel as stand-alone or first treatment options performed
without other physical interventions directed toward increasing vessel
patency, or such treatments may done in conjunction with other
interventional approaches, such as treatment of a site previously treated
or contemporaneously treated to inhibit or prevent restenosis.

[0010] Embodiments of the invention include a method and devices for
treating stenosis or inhibiting restenosis in an artery or vein by
delivering a therapeutic agent into the artery or vein and enhancing
absorption of the therapeutic agent into a wall of the artery or vein
using ultrasound energy. Such method includes advancing a distal end of a
combined ultrasound/drug delivery catheter to an area of stenosis or
restenosis in an artery or vein; delivering a stenosis inhibiting
therapeutic agent into the artery or vein from the ultrasound/drug
delivery catheter; and activating the ultrasound catheter to emit
ultrasound energy while delivering the therapeutic agent.

[0011] Another embodiment of the present invention includes a method and
devices for treating or inhibiting restenosis in an artery or vein by
first delivering ultrasound energy to the vessel wall and exposing the
vessel wall to ultrasound energy using an ultrasound catheter. After
exposing the vessel wall to ultrasound energy, a stenosis inhibiting
therapeutic agent is delivered into the artery or vein. Delivery of such
a therapeutic agent can be accomplished with the same device or through a
separate drug delivery catheter. A separate catheter to deliver
therapeutic drug may be an ultrasound energy catheter or any other drug
delivery catheter.

[0012] Alternatively, the present invention also includes a method and
devices for treating or inhibiting restenosis in an artery or vein by
delivering ultrasound energy from an external ultrasound energy source
from outside of the body, through the skin (also known as transcutaneous
approach). After exposing the vessel wall to ultrasound energy from the
external source, a stenosis inhibiting therapeutic agent is delivered
into the artery or vein. Delivery of such therapeutic agent can be
accomplished by using an endovascular drug delivery catheter.

[0013] These methods and devices for treating stenosis or inhibiting
restenosis are such that the delivery of the ultrasonic energy either
from an external ultrasound energy source or from an endovascular
ultrasound device causes vasodilatation within vessel wall. In typical
embodiments of the method, the therapeutic agent is delivered from the
ultrasound drug delivery catheter at or near the distal end, and
activating the ultrasound drug delivery catheter converts the therapeutic
agent into droplets.

[0014] In various embodiments, the therapeutic agent may be dispersed at a
constant rate or a variable rate. In some embodiments, the therapeutic
agent is delivered from a plurality of outlet ports that are arrayed
around the distal end of the ultrasound catheter. In other embodiments,
the therapeutic agent may be delivered from a perfusion porous balloon, a
balloon coated with the therapeutic agent or from an expandable mesh
coated with the therapeutic agent located at the distal end of the
ultrasound drug delivery catheter. In still other embodiments, the
therapeutic agent is delivered in radial fashion through at least one of
the outlet ports located in the distal tip of the ultrasound drug
delivery catheter or outlet ports located on the ultrasound catheter body
proximal to the distal tip. In another embodiment, the therapeutic agent
can be delivered following delivery of ultrasound energy to the vessel
wall in any desirable fashion, utilizing the same or different ultrasound
catheter or employing these methods using any conventional drug delivery
catheter.

[0015] Some embodiments of the method and devices for treating stenosis or
inhibiting restenosis further include delivering an irrigation fluid
through the ultrasound catheter during the ultrasound catheter
activation. In some of these embodiments, the irrigation fluid and the
therapeutic agent are delivered together in a mixture; in other
embodiments, the irrigation fluid is delivered separately from the
therapeutic agent. In these latter embodiments, the method may include
introducing an irrigation fluid via one or more outlet ports on the
ultrasound/drug delivery catheter that are separate from one or more
therapeutic agent outlet ports.

[0016] The scopes of the embodiments of the method and devices include the
application of any therapeutic agent to a target site, such agents
considered to be medically beneficial to the patient being treated, and
examples of such agents are provided in the detailed description. The
therapeutic agent or agents may be in any of the following forms: liquid,
powder, particle, microbubbles, microspheres, nanospheres, liposomes and
combinations thereof.

[0017] Embodiments of the method and devices for treating stenosis or
inhibiting restenosis may further include repositioning or moving the
ultrasound drug delivery catheter during ultrasound energy activation and
a therapeutic agent delivery to further enhance drug delivery.

[0018] Embodiments of the method and devices for treating stenosis or
inhibiting restenosis may further include a blood flow protection
device(s), such as balloon devices that are independent from ultrasound
delivery device or coupled to the ultrasound catheter, within the artery
or vein to prevent the therapeutic agent from flowing down stream. In
such embodiments, expanding the blood flow protection device includes
expanding it in at least one of the locations of distal to the ultrasound
catheter distal tip or proximal to the ultrasound catheter distal tip.
These method embodiments may further include removing the therapeutic
drug trapped by the blood flow protection device(s) from the body.

[0019] Embodiments according to the present invention for treating
stenosis or inhibiting restenosis may further include delivering
therapeutic agent after the delivery of ultrasound energy: first exposing
the treatment area to ultrasound energy either from an external
ultrasound source (such as an ultrasound transducer) or from an
endovascular ultrasound catheter, and after ultrasound, exposing to the
vessel wall, arterially or venously delivering the therapeutic agent o
the treatment area.

[0020] In some embodiments of the present invention for treating stenosis
or inhibiting restenosis, advancing the ultrasound drug delivery catheter
includes advancing it in a manner selected from monorail, over-the-wire,
and without the use of a guidewire. In various embodiments, the
ultrasound catheter can operate in continuous mode, pulse mode and a
combination continuous/pulse mode, and in some embodiments the ultrasound
energy can be modulated. Modulation of ultrasound energy may include
modulation of voltage, current, frequency or pulse parameters such as
ultrasound energy ON/OFF time or any combination of all. In still other
embodiments, advancing the ultrasound/drug delivery catheter may include
contacting the wall of the blood vessel with the catheter.

[0021] Some embodiments of the present invention for treating stenosis or
inhibiting restenosis further include performing an angioplasty or
venoplasty procedure before, during or after delivery of the therapeutic
agent and ultrasound energy, wherein the angioplasty or venoplasty
procedure can be balloon angioplasty or venoplasty, stent placement,
atherectomy, laser angioplasty or venoplasty, ultrasound angioplasty or
venoplasty, cryoplasty, or a combination of these procedures. In various
embodiments, performing the angioplasty or venoplasty procedure includes
advancing a balloon device over a guidewire to the area of stenosis or
restenosis in the artery or vein, wherein the combined ultrasound drug
delivery catheter is advanced over the same guidewire.

[0022] In various other embodiments of the present invention, treating
stenosis or inhibiting restenosis further include performing an
angioplasty or venoplasty procedure before, during or after delivery of
the ultrasound energy and delivery of therapeutic agent is performed
separately from delivering ultrasound energy, either during or after
delivering ultrasound energy.

[0023] In another aspect, the present invention provides a method for
treating stenosis and inhibiting restenosis in an artery or vein by
dilating the artery or vein, delivering a therapeutic agent to the artery
or vein, and at the same time enhancing absorption of the therapeutic
agent using ultrasound energy. In this aspect, the method may include
advancing a distal portion of a combined dilation, ultrasound, drug
delivery catheter to an area of stenosis or restenosis in an artery or
vein; expanding an arterial dilator of the catheter to dilate the artery
or vein at the area of stenosis or restenosis; delivering a stenosis
inhibiting therapeutic agent into the artery or vein through the
catheter; and activating the catheter to emit ultrasound energy while
delivering the therapeutic agent

[0024] In still another aspect, the present invention provides a method
and devices for treating stenosis and inhibiting restenosis in an artery
or vein by delivering a therapeutic agent to the artery or vein and
enhancing absorption of the therapeutic agent using ultrasound energy. In
this aspect, the method may include advancing a distal portion of a
combined ultrasound/drug delivery catheter to an area of stenosis or
restenosis in an artery or vein; expanding an expandable member, such as
a balloon, coupled with the catheter at least one of distal or proximal
to a drug delivery portion of the catheter, to prevent the therapeutic
agent from flowing at least one of proximally or distally beyond the
expandable member; delivering a stenosis inhibiting therapeutic agent
into the artery or vein through the catheter; and activating the catheter
to emit ultrasound energy while delivering the therapeutic agent. In
various of these particular embodiments, expanding the expandable member
includes expanding a member either distal to or proximal to the drug
delivery portion of the catheter. In some embodiments, expanding the
expandable member includes expanding two expandable members, one distal
to and one proximal to the drug delivery portion of the catheter.

[0025] In still another aspect, the present invention provides a method
and devices of treating vulnerable plaque that includes introducing an
ultrasound dispersed therapeutic agent to a treatment area: and
activating ultrasound energy to cause passage of the therapeutic drug
into the vessel wall.

[0026] In still another aspect, the invention provides a method and
devices for treating stenosis or inhibiting restenosis in a totally
occluded artery or vein by delivering a therapeutic agent into the artery
or vein and enhancing absorption of the therapeutic agent into a wall of
the artery or vein using ultrasound energy. This embodiment may include
advancing a distal end of a combined ultrasound/drug delivery catheter to
an area of a totally occluded artery or vein; delivering a stenosis
inhibiting therapeutic agent into the artery or vein from the
ultrasound/drug delivery catheter; and activating the ultrasound catheter
to emit ultrasound energy while delivering the therapeutic agent. In some
of these embodiments, advancing a distal end of a combined
ultrasound/drug delivery catheter to an area of stenosis or restenosis in
an artery or vein is performed without ablation or removal of material.
In other embodiments, treating stenosis or inhibiting restenosis in an
artery or vain by delivering a therapeutic agent into the artery or vain
and enhancing absorption of the therapeutic agent into a wall of the
artery or vain using ultrasound energy further includes ablation or
removal of material.

[0027] Embodiments of the inventive therapeutic methodology will now be
summarized with reference to an approach to antistenotic treatment of
blood vessels more broadly, whether the treatment site is being subjected
to a first treatment, a repeat treatment following any other antistenotic
treatment, a follow up treatment to prevent or inhibit restenosis
following a previous antistenotic treatment of any kind, and whether the
treatment site is totally occluded, partially occluded, experiencing
in-stent occlusion, vein graft occlusion, or artificial graft occlusion,
or diagnosed as being vulnerable to occlusion, or any combination
thereof.

[0028] Embodiments of the inventive methods and devices provided herein
relate to approaches to antistenotic treatment at a target site in a
blood vessel, a vein or an artery, for example, by using ultrasound
energy to enhance delivery of a therapeutic agent. The site of treatment
may be a site that has not been previously treated, the treatment
embodiment thereby being a first therapeutic intervention, or the
treatment site may have been treated before by another interventional
method, or even by the present inventive method (i.e., a repeat
treatment). In some embodiments of the method, the ultrasound-enhanced
therapeutic agent is applied in close temporal conjunction with other
interventional methods, such as angioplasty or venoplasty. In various
embodiments the method may be applied to vessels with a range of stenosis
or plaque buildup, ranging from mild occlusion to total occlusion. In
other embodiments, the method may be applied to treatment sites in order
to impede or prevent restenosis following an earlier treatment. In still
other embodiments, the method may be applied to sites identified as being
vulnerable to stenotic processes. The scope of embodiments of the method
includes the application of any therapeutic agent to a target site, such
agents considered to be medically beneficial to the patient being
treated.

[0029] Embodiments of the method and devices of antistenotic treatment
include positioning a distal end of a combined ultrasound drug delivery
catheter proximate the treatment site in a blood vessel. This positioning
of the catheter proximate the site may be accomplished without ablating
or removing any plaque material that may be present. Embodiments of the
method further include delivering a fluid formulation including a
therapeutic agent to the site from the ultrasound drug delivery catheter;
and emitting ultrasound energy from the ultrasound catheter while
delivering the therapeutic agent. In some embodiments of the method, a
dilator may also be positioned at the treatment site and dilated, such
dilation increasing the efficiency and consistency of ultrasound delivery
to areas of the internal vessel surface at the treatment site. While, as
noted above, some embodiments of the method do not include direct
physical or energy delivery attack on plaque, other embodiments may
include ablating, removing, or compressing plaque material at the
treatment site.

[0030] With regard to aspects of the delivery of ultrasound energy to the
target site, the ultrasound energy source (such as an external ultrasound
transducer or endovascular ultrasound catheter or ultrasound drug
delivery catheter) may be operated in a continuous mode, a pulse mode, or
in any combination or sequence thereof; further the ultrasound energy may
be modulated. In general, the emitted ultrasonic energy is sufficient to
cause vasodilatation of the blood vessel and/or sonoporation within cells
of the vessel wall proximate the target site, preferably, without causing
vascular damage. Alternatively, ultrasound energy may be delivered
separately from delivering therapeutic agent using the same device or a
different device. A different conventional drug delivery catheter may be
used together with ultrasound delivery catheter.

[0031] As noted above, some embodiments may include repeated applications,
or multiple applications at the same site, or at another portion of a
larger treatment site. Thus, for example, embodiments of the method may
include repositioning the ultrasound drug delivery catheter; and
repeating the step of emitting ultrasonic energy. Positioning the
ultrasound drug delivery catheter at the target site may include
positioning the catheter nearby the target site, or it may include
contacting the vessel wall at the site. In some embodiments, the
contacting may be optimized by dilation of the treatment site, so as to
optimize and make uniform a therapeutically effective contact between the
ultrasound catheter and the target tissue.

[0032] Some embodiments include advancing an ultrasound/drug delivery
catheter to the treatment site either prior to or in conjunction with
appropriate positioning of the catheter for treatment of the site.
Advancing the catheter may be accomplished by conventional approaches
either with or without a guidewire. Guidewire-assisted methods may
include any approach, such as over-the-wire, or monorail deployment.

[0033] Some embodiments of the method and devices of antistenotic
treatment may further include expanding a first blood flow prevention
member coupled to the catheter at a site proximate the drug delivery
portion of the catheter to a degree of expansion sufficient to prevent
the therapeutic agent from flowing in the vessel beyond the expandable
member. In these embodiments, a blood flow protection member, such as a
balloon, may be disposed distal to (typically, downstream from) a drug
delivery portion of the catheter. In other embodiments, a blood flow
protection member may be disposed proximal to (typically, upstream from)
a drug delivery portion of the catheter. In still other embodiments, two
blood flow protection members may be disposed proximate the drug delivery
portion of the catheter, one member disposed distally, the other disposed
proximally. In some embodiments of the method that make use of blood flow
prevention members in order to contain released drug into a confined
vascular space, the method may further include removing such trapped drug
from the body after the ultrasonic treatment, and before collapsing the
blood flow prevention members, allowing free flow of blood through the
treated portion of the vessel. In yet another embodiment, therapeutic
agent may be delivered to the vessel wall in conjunction with delivering
ultrasound energy or separately after exposing the treatment area to
ultrasound energy.

[0034] With regard to the formulation that includes the therapeutic agent
that is being delivered by embodiments of the method, such formulation is
typically in the form of a liquid, either aqueous, organic, or a
combination thereof, such as an emulsion. Formulations may further
include dispersions of powders or particles, microbubbles, microspheres,
nanospheres, liposomes, or any combination thereof The emitted ultrasound
energy, per embodiments of the method, is sufficient to convert the
formulation including the therapeutic agent into droplets, microdroplets,
or aerosols. The therapeutic agent within its formulation may be
dispersed from a drug delivery portion of the catheter at a constant or a
variable rate, or any combination thereof

[0035] Embodiments of the method and devices provided herein may further
include holding the formulation with the therapeutic agent in a reservoir
associated with the ultrasound/drug delivery catheter prior to the
delivery step. These embodiments may include delivering the therapeutic
agent formulation through one or more outlet ports in communication with
the reservoir. In some embodiments, the reservoir may include a balloon
or a mesh upon which the therapeutic agent is coated, and from which the
agent is released or eluted.

[0036] Some embodiments of the method and devices provided herein further
include delivering an irrigation fluid from the ultrasound catheter while
emitting ultrasound energy. In some of these embodiments, the irrigation
fluid and the therapeutic agent formulation are delivered together in a
common mixture; in other embodiments, the irrigation fluid and the
formulation including the therapeutic agent are delivered as separate
fluids. When delivered separately, the irrigation fluid and the
therapeutic agent formulation may be delivered from separate respective
outlet ports.

[0037] Some embodiments of the method and devices further include
performing an angioplasty procedure before, during or after delivery of
the therapeutic agent and ultrasound energy, as summarized above. The
angioplasty or venoplasty procedure may be of any conventional type, such
as balloon device, stent placement, atherectomy, laser angioplasty or
venoplasty, ultrasound angioplasty or venoplasty, cryoplasty, or any
combination of such procedures. In some embodiments of this method,
performing the angioplasty or venoplasty procedure may include advancing
a balloon device over a guidewire to the target site, wherein the
combined ultrasound/drug delivery catheter is advanced over the same
guidewire.

[0038] Thus, one aspect of the invention includes an antistenotic
treatment at a target site in a blood vessel that includes positioning a
distal end of a combined ultrasound/drug delivery catheter to the site,
delivering a fluid formulation including a therapeutic agent to the site
from the ultrasound/drug delivery catheter, and emitting ultrasound
energy from the ultrasound catheter while delivering the therapeutic
agent, and performing an angioplasty or venoplasty procedure at the
target site.

[0039] Another aspect of the invention includes an antistenotic treatment
at a target site in a blood vessel that includes positioning a distal end
of a combined ultrasound/drug delivery catheter to the site, emitting
ultrasound energy from the ultrasound catheter without delivering the
therapeutic agent, and then delivering a therapeutic agent to the site
from the ultrasound/drug delivery catheter after first delivering
ultrasound energy to the vessel wall.

[0040] In another aspect, the invention provides a method and devices for
treating stenosis or inhibiting restenosis which includes emitting
ultrasound energy from an ultrasound energy source and delivering a
therapeutic agent intravenously into the human body.

[0041] In still another aspect, the invention provides a method and
devices for treating stenosis or inhibiting restenosis which includes
emitting ultrasound energy from an ultrasound energy source and
delivering a therapeutic agent together with a contrast agent (either
100% or diluted with a conventional saline NaCl solution) into the artery
or vein to the treatment location.

[0042] In still another aspect, the invention provides a method and
devices for treating stenosis or inhibiting restenosis which includes
emitting ultrasound energy from an ultrasound energy source and
delivering a therapeutic agent in solution with Carbamide (an organic
compound with the chemical formula (NH2)2CO) into the artery or
vein to the treatment location.

[0043] The scope of the embodiments and methods described herein include
the application of any therapeutic agent to a target site for a period of
time that is considered to be medically beneficial to the patient being
treated. Any therapeutic drug may be exposed to the vessel for about one
second to one hour to assure a maximum benefit of the delivered drug.

[0044] Suitable therapeutic agent(s) maybe delivered to the treatment area
in variety of different forms and mixtures, either with or without
ultrasound, and with or without interventional procedure.

[0045] Some embodiments of the method and devices of antistenotic
treatment may further include removal of the therapeutic drug outside of
the body, to avoid adverse systemic effects that may be caused by the
therapeutic drug.

[0046] All these methods and devices for treating stenosis or inhibiting
restenosis in an artery or vein by enhancing permeability of the vessel
wall using ultrasound energy and delivering a therapeutic agent into the
artery or vein may be achieved with endovascular or transcutaneous
techniques of delivery ultrasound energy. The therapeutic drug may be
delivered to the treatment site before, during and after ultrasound
energy delivery.

[0047] Some other embodiments of the present invention include devices
capable to further improve vessel permeability utilizing ultrasound
energy propagated along a flexible member in the form of longitudinal
waves, surface (radial or elliptic) waves and shear (transverse) waves,
among other waves, simultaneously.

[0048] In another embodiment, the invention provides devices and methods
for ablating plaque, crossing Chronic Total Occlusions (CTO), as well as
dissolving and removing blood clots and thrombus. This embodiment may
include advancing a distal end of an ultrasound delivery device into the
vessel, vein or other locations where plaque or blood clots are located,
activating the ultrasound catheter to emit radial ultrasound energy, and
applying aspiration to further dissolve and remove blood clots outside
the patient body. Use of therapeutic drug and/or microbubbles may enhance
plaque and blood clots dissolving and removal process.

[0049] In patients undergoing endovascular procedures involving a vascular
obstruction removal or administration of therapeutic drugs, use of
ultrasound energy may be beneficial in the delivery of liquid medicament
to further facilitate the distribution, delivery, absorption and/or
efficacy of the medicament to improve clinical outcomes. Various
ultrasonic catheter devices have been developed for use in ablating or
otherwise removing obstructive material from blood vessels. For example,
ultrasound devices with flexible ultrasound members for tissue ablation
(either with or without therapeutic drugs) have been discussed in the
prior art. Known devices enable translation of vibrations from the
transducer to the flexible probe causing the probe to oscillate
longitudinally or transversely. Longitudinal vibratory movement of the
distal head or probe causes disintegration and ablation of the adjacent
lesion while simultaneously delivering therapeutic drugs. Examples of
such devices include U.S. Pat. Nos. 6,689,086 and 6,929,632 (both by
Nita, et al). Other examples of devices utilizing longitudinal vibrations
are described in U.S. Pat. Nos. 6,855,123; 6,942,677; 7,137,963;
7,297,131; 7,393,338; 7,621,929; 7,955,293; 8,133,236 and US Publication
No. 2008/0108937 (all by Nita, et al.). Unlike longitudinal vibrations,
transverse vibration emits a transverse ultrasonic energy along the
length of the probe body so that a plurality of transverse nodes and
anti-nodes are formed along the length of the probe. Examples of such
devices include U.S. Pat. Nos. 6,524,251; 6,551,337; 6,652,547;
6,660,013; 6,695,781; 6,733,451; 6,866,670; 7,494,468; and 7,503,896 (all
by Rabiner, et al.). While the longitudinal waves oscillate in the
longitudinal direction or the direction of wave propagation, transverse
waves oscillate perpendicular to the direction of propagation. Transverse
waves are relatively weak compared to longitudinal waves and are known to
not effectively propagate through liquids. Also, transverse vibrations
are known to produce unwanted stress along the ultrasound transmission
member, often causing breakage of the ultrasound transmission member.
While longitudinal waves (as described in the prior art) are powerful,
their ability to deliver ultrasound energy to the surrounding vessel wail
is limited to the vibrating tip area. Therefore, longitudinal and
transverse vibrations are limited in inducing uniform cellular changes
along the treated vessel wall to further facilitate drug therapies.

[0050] The present invention provides methods and devices configured to
deliver ultrasound surface waves or radial vibrational energy along an
ultrasound transmission member to the surrounding tissue, to either small
or large vessels or other cavities, and consequently increasing vessel
drug uptake. Such devices provide a desired level of ultrasound energy to
induce cellular changes while preventing vascular damage and reducing the
potential of breakage for the ultrasound transmission member.

[0052] FIGS. 2A, B, and 2C show various views of embodiments of ultrasound
catheters for delivering a therapeutic agent to inhibit stenosis.

[0053] FIG. 2A shows a side view of an ultrasound-enhanced drug delivery
catheter.

[0054] FIG. 2B shows a view of a longitudinal cross section of an
embodiment of an ultrasound-enhanced drug delivery catheter.

[0055] FIG. 2C shows a view of a longitudinal cross section of an
alternative embodiment of an ultrasound-enhanced drug delivery catheter.

[0056] FIGS. 3A, 3B, and 3C show side views of embodiments of an
ultrasound-enhanced drug delivery catheter at a stenosis therapy site.

[0057] FIG. 3A shows an embodiment of the ultrasound catheter with holes
at the distal tip of the catheter for the delivery of a therapeutic
agent.

[0058] FIG. 3B shows an embodiment of an ultrasound catheter with ports in
the wall of the catheter body for the delivery of a therapeutic agent.

[0059] FIG. 3C shows an embodiment of an ultrasound catheter with
therapeutic agent delivery sites in the form of holes at the distal tip
of the catheter and delivery ports in the wall of the catheter body.

[0060] FIG. 4A shows an embodiment of an ultrasound-enhanced drug delivery
catheter positioned for a balloon angioplasty or venoplasty procedure
prior to ultrasound-enhanced drug delivery to a stenotic site.

[0061] FIG. 4B shows an embodiment of the ultrasound-enhanced drug
delivery catheter delivering therapeutic agent to a stenotic site
following a balloon angioplasty or venoplasty procedure.

[0062] FIG. 5 shows an embodiment of an ultrasound-enhanced drug delivery
catheter delivering therapeutic agent to a stenotic site, the catheter
further associated with an expanded. distal protection balloon device
positioned at the distal end of a guidewire, the expanded balloon filling
the vessel lumen and preventing downstream the flow of therapeutic agent.

[0063] FIG. 6 shows an embodiment of an ultrasound-enhanced drug delivery
catheter with and an additional sheath for delivering a therapeutic agent
to a vessel to inhibit restenosis.

[0066] FIG. 8A shows a general view of an ultrasound-enhanced drug
delivery using an external ultrasound source and a transcutaneous method
to deliver ultrasound energy to the treatment area.

[0067] FIG. 8B shows an embodiment of an ultrasound-enhanced drug delivery
using external ultrasound source and a transcutaneous method to deliver
ultrasound energy to the treatment area, and further showing endovascular
catheter to deliver a therapeutic agent.

[0068] FIG. 9 shows an ultrasound device having a flexible distal member
to deliver ultrasound energy to the treatment area to improve vessel drug
permeability.

[0069] FIG. 10 shows an ultrasound device with a distal ultrasound
transmission member according to another embodiment of the present
invention.

[0070] FIG. 11 is a partial cross-sectional view of the proximal portion
of the ultrasound device shown in FIG. 10.

[0071] FIGS. 12-15 show different embodiments of the distal ultrasound
transmission member shown in FIG. 10.

DETAILED DESCRIPTION OF THE INVENTION

[0072] The present application provides new methods and devices to improve
the treatment of vascular stenosis and re-stenosis using ultrasound
technology to enhance delivery of therapeutic agents directly to a
targeted therapeutic site, such as astenotic site on an artery or vein
wall. These methods may be understood as forms of anti-stenosis
treatment, which may include treatment of a stenotic site to reduce
plaque and to increase the patency of the afflicted vessel, or it may
also include treatment of a site previously treated or contemporaneously
treated to inhibit or prevent restenosis. Aspects of the invention,
including devices and the types of therapeutic agents whose efficacy may
be enhanced by the provided technology will be described first in general
terms, and then, further below, will be described in the context of FIGS.
1-15.

[0073] The methods described herein employ endovascular sonophoresis and
induce vasodilatation, a process that creates micro-indentations in a
vessel wall during ultrasound energy delivery; these indentations
increase vessel wall permeability and permit a higher level of
therapeutic agent delivery to the target cell interior. When ultrasound
energy is delivered at a frequency range of 1 kHz-10MHz and at power
below 20 watts to the vessel wall, the sound. waves transiently disrupt
the integrity of the cell membranes without creating permanent damage to
the vessel wall or surrounding tissue. In a typical embodiment of the
invention, for example, ultrasound energy from a source in contact or in
proximity to a vessel wall, at a frequency of about 20 kHz and a power of
less than about 10 watts is used to induce sonoporation and
vasodilatation. Power levels above 20 watts may cause permanent damage to
the vessel wall such as thermal damage, necrosis and vessel rupture when
ultrasound energy is delivered by an endovascular catheter. Power levels
above 20 watts may also cause skin burns or wounds when ultrasound energy
is delivered transcutaneously through the skin.

[0074] As used herein, "power" of the endovascular catheter delivering
ultrasound energy refers to watts of power delivered by the distal end or
tip of the catheter per mm' of the tip's or distal end's cross-sectional
area. For transcutaneous delivery of ultrasound energy, "power" refers to
a total amount of watts of power of the ultrasound device per cm2 of
the contact area between the device and the skin.

[0075] Sonoporation uses the interaction of ultrasound energy with the
presence of locally or systemically delivered drugs to temporarily
permeabilize the cell membrane allowing for the uptake of DNA, drugs, and
other therapeutic compounds from the extracellular environment. This
membrane alteration is transient, leaving the compound trapped inside the
cell after ultrasound exposure. Sonoporation combines the capability of
enhancing gene and drug transfer with the possibility of restricting this
effect to the desired area and the desired time. Thus, sonoporation is a
promising drug delivery and gene therapy technique, limited only by a
full understanding regarding the biophysical mechanism that results in
the cell membrane permeability change.

[0076] Oscillation of delivered therapeutic agents is considered to be a
primary mechanism causing sonoporation. However, inertial cavitation,
microstreaming, shear stresses, and liquid jets as a result of linear and
nonlinear oscillations all may be causal mechanisms contributing to
sonoporation as well. Propagating ultrasound pressure waves have an
impact in regulating endothelial cell function, cell morphology,
metabolism, and gene expression. Fluid shear stress caused by propagating
ultrasound waves induces a rapid, large, and sustained increase in Nitric
Oxide activity. In the very acute setting (seconds) of shear stress,
calcium-activated potassium channels open and increase Nitric Oxide
production. Nitric Oxide contributes to vessel dilation by inhibiting
vascular smooth muscle constriction. This Nitric Oxide delivery may
improve targeted therapeutic delivery into vascular tissues.

[0077] In some embodiments of the invention, the method and devices may
include converting a therapeutic agent from liquid form into spray via
ultrasound, a method known as nebulization that converts the low
viscosity drug into an ultra fine spray as it exits from the catheter
tip. Thus, this allows a rapid cellular uptake of drug and enables it to
easily pass through the hydrophobic barrier of cell membranes. As the
drug is delivered through the catheter, it is mechanically pulverized
into droplets from the vibrating distal end of the catheter, further
increasing permeation of the drug into the vessel wall.

[0078] In one aspect, methods and improved devices are provided for
inhibiting stenosis, restenosis, and/or hyperplasia concurrently with
and/or after intravascular intervention. As used herein, the term
"inhibiting" means any one of reducing, treating, minimizing, containing,
preventing, curbing, eliminating, holding back, or restraining. In some
embodiments, ultrasound enhanced delivery of therapeutic agents to a
vessel wall with increased efficiency and/or efficacy is used to inhibit
stenosis or restenosis. Such a method may also minimize drug washout and
provide minimal to no hindrance to endothelialization of the vessel wall.

[0079] As used herein, "treatment site" refers to an area in a blood
vessel or elsewhere in the body that has been or is to be treated by
methods or devices of the present invention. Although "treatment site"
will often be used to refer to an area of a vessel wall that has stenosis
or restenosis ("a stenotic site"), the treatment site is not limited to
vascular tissue or to a site of stenosis. The term "intravascular
intervention" includes a variety of corrective procedures that may be
performed to at least partially resolve a stenotic, restenotic, or
thrombotic condition in a blood vessel, usually an artery or vein of a
human body. Commonly, at least in current practice, the therapeutic
procedure may also include balloon angioplasty or venoplasty. The
corrective procedure may also include directional atherectomy, rotational
atherectomy, laser angioplasty or venoplasty, stenting, or the like,
where the lumen of the treated blood vessel is enlarged to at least
partially alleviate a stenotic condition which existed prior to the
treatment. The treatment site may include tissues associated with bodily
lumens, organs, or localized tumors. In one embodiment, the present
devices and methods reduce the formation or progression of restenosis
and/or hyperplasia that may follow an intravascular intervention. A
"lumen" may be any blood vessel in the patient's vasculature, including
veins, arteries, aorta, and particularly including coronary and
peripheral arteries, as well as previously implanted grafts, shunts,
fistulas, and the like. In alternative embodiments, methods and devices
described herein may also be applied to other body lumens, such as the
biliary duct, which are subject to excessive neoplastic cell growth.
Examples of internal corporeal tissue and organ applications include
various organs, nerves, glands, ducts, and the like.

[0080] As used herein, "therapeutic agent" includes any molecular species,
and/or biologic agent that is either therapeutic as it is introduced to
the subject under treatment, becomes therapeutic after being introduced
to the subject under treatment, for example by way of reaction with a
native or non-native substance or condition, or any other introduced
substance. Examples of native conditions include pH (e.g., acidity),
chemicals, temperature, salinity, osmolality, and conductivity; with
non-native conditions including those such as magnetic fields,
electromagnetic fields (such as radiofrequency and microwave and
ultrasound. In the present application, the chemical name of any of the
therapeutic agents is used to refer to the compound itself and to
pro-drugs (precursor substances that are converted into an active form of
the compound in the body), and/or pharmaceutical derivatives, analogues,
or metabolites thereof (bio-active compound to which the compound
converts within the body directly or upon introduction of other agents or
conditions (e.g., enzymatic, chemical, energy), or environment (e.g.,
pH).

[0081] The scope of the invention includes the use of any therapeutic
agent whose medicinal effectiveness may be enhanced by the use of
ultrasonic energy, as described herein. For the purposes of illustration,
a number of therapeutic agent classes will be identified in order to
convey an understanding the invention. These classes of agents and the
specific listed agents are not intended to limit the scope or practice of
the invention in any way; the scope of the invention includes any
therapeutic agent that may be considered beneficial in the treatment of a
patient. Further, these agents may be delivered by any appropriate
modality, as for example, by intra-arterial direct injection,
intravenously, orally, or a combination thereof.

[0084] In some embodiments, the method and devices may include introducing
anti-cancer therapeutic agents for promoting intracellular activation by
irradiating the vessel wall cells with ultrasound to cause passage of the
these drug into the vessel wall to inhibit stenosis and restenosis. In
some embodiments, for example, an anti-angiogenesis agent may be used to
inhibit stenosis or restenosis.

[0085] Ultrasound enhancement provided by the apparatus and method and
devices of the present invention may be of particular benefit when the
therapeutic agent being administered is highly toxic. Specific examples
of such drugs are the anthracycline antibiotics such as adriamycin and
daunorubricin. The beneficial effects of these drugs relate to their
nucleotide base intercalation and cell membrane lipid binding activities.
This class of drugs has dose limiting toxicities due to undesirable
effects, such as bone marrow suppression, and cardiotoxicity.

[0088] Agents with alkylator activity include a group of compounds that
include heavy metal aikylators (platinum complexes) that act
predominantly by covalent bonding and "non-classic alkylating agents" are
also within the scope of the present invention. Such agents typically
contain a chloromethyl groups and an important N-methyl group. Such other
agents include Amsacrine (m-AMSA, msa, Acridinylanisidiale,
4'-)(9-acridinylamins) methanesulfin-m-anesidide, Carboplatin
(Paraplatin, Carboplatinum, CBDCA), Cisplatin (Cesplatinum), Dacabazine
(DTIC, DIC dimethyltricizenormidazoleconboxamide), Hexamethylmelanine
(HMM, Altretanine, Hexalin) and Procarbazine (Matulane, Natulanan).

[0094] The drugs that may be useful in preventing in-stent restenosis fall
into four major categories; anti-neoplastics, immunosupressives,
migration inhibitors, and enhanced healing factors.

[0095] Anti-proliferative compounds include Paclitaxel, QP-2, actinomycin,
statins and many others. Paclitaxel was originally used to inhibit tumor
growth by assembling microtubules that prevent cells from dividing. It
has also recently been observed to attenuate neointimal growth.

[0096] Immunosupressives are generally used to prevent the immune
rejection of allogenic organ transplants. The general mechanism of action
of most of these drugs is to stop cell cycle progression by inhibiting
DNA synthesis. Everolimus, Sirohmus, Tacrolimus (FK-506), ABT-578,
interferon, dexamethasone, and cyclosporine all fall into this category.
The Sirolimus derived compounds appear especially promising in their
ability to reduce intimal thickening.

[0097] Migration inhibitors are aimed at preventing endothelial cell
migration to the inside of the stent. Once smooth muscle cells migrate to
the luminal side of the stent, they can produce extracellular matrix and
begin to occlude blood flow. Therefore, inhibiting their migration can
have great therapeutic applications for preventing in-stent restenosis.
Examples of these compounds are batimastat and halofuginone. Batimastat,
for example, is a potent inhibitor of matrix metalloproteinase enzymes.
It can prevent the matrix degradation that is necessary for cells to free
themselves to move. If the cells cannot move, they cannot invade the
stent area.

[0098] Enhanced Healing Factors: Vascular endothelial growth factor (VEGF)
promotes healing of the vasculature. In the context of stents, this would
heal the implantation site and reduce platelet sequestration due to
injury related chemotaxis. Nitrous oxide donor compounds may also
replicate this effect. Healing of the vessel wall seems o be the gentlest
approach to preventing ISR, but healing factors are still in the early
stages of development for this application.

[0099] Sirolimus (rampamycin) and Paclitaxel are the two drugs that are
commonly used in drug eluting stents. Sirolimus is a macrocyclie lactone
immunosuppressive agent that inhibits the cell division cycle and
cellular proliferation by promoting kinase activation and halting the
cellular growth phase. Paclitaxel also inhibits the cell cycle, but works
via a different mechanism than Sirolimus. Paclitaxel binds to
microtubules in dividing cells and causes them to assemble, thereby
preventing mitosis. Paclitaxel is in the anti-neoplastic family of
compounds. Together, Paclitaxel and Sirolimus are two of the most
promising drugs for use in stents, as several others have run into
problems with lumen loss, late thrombosis, delayed restenosis. and
aneurysm formation.

[0100] For the removal of blood clots and thrombus, examples of
therapeutic agents may include (i) tissue plasminogen activator, tPA,
BB-10153, rTPA, Urokinease, Streptokinase, Alteplase and Desmoteplase,
(ii) antiplatelet agents such as aspirin, Clopidorgel and Ticclopidine,
and (iii) GIIb/IIIa inhibitors, such as Abciximab, Tirofiban and
Eptifibatide.

[0101] The devices of the present invention may be configured to release
or make available the therapeutic agent at one or more treatment phases,
the one or more phases having similar or different performance (e.g.,
delivery) profiles. The therapeutic agent may be made available to the
tissue at amounts which may be sustainable, intermittent, or continuous;
in one or more phases and/or rates of delivery; effective to reduce any
one or more of smooth muscle cell proliferation, inflammation, immune
response, hypertension, or those complementing the activation of the
same. Any one of the at least one therapeutic agents may perform one or
more functions, including preventing or reducing proliferative/restenotic
activity, reducing or inhibiting thrombus formation, reducing or
inhibiting platelet activation, reducing or preventing vasospasm, or the
like.

[0102] The total amount of therapeutic agent made available to the tissue
depends in part on the level and amount of desired therapeutic result.
The therapeutic agent may be made available at one or more phases, each
phase having similar or different release rate and duration as the other
phases. The release rate may be pre-defined. In an embodiment, the rate
of release may provide a sustainable level of therapeutic agent to the
treatment site. In another embodiment, the rate of release is
substantially constant. The rate may decrease and/or increase as desired.

[0103] These therapeutic agents may be provided and or delivered to the
body in any conventional therapeutic form or formulation, such as, merely
by way of example: liquid, powder, particle, microbubbles, microspheres,
nanospheres, liposomes and/or combinations thereof

[0104] Some embodiments of the invention may also include delivering at
least one therapeutic agent and/or optional compound within the body
concurrently with or subsequent o an interventional treatment. More
specifically, the therapeutic agent may be delivered to a targeted site
that includes the treatment site concurrently with or subsequent to the
interventional treatment. By way of example: [0105] a. A therapeutic
agent may be delivered to the treatment site as a stand-alone therapy in
treatment of native stenosis or restenosis, without any other
contemporaneous remedy or treatment such as provided by a physical or
mechanical dilation. [0106] b. A therapeutic agent may be delivered to
the treatment site as the only therapy in treatment of stenosis or
restenosis in grafts. [0107] c. A therapeutic agent may he delivered to
the treatment site following any suitable interventional procedure.
[0108] d. A therapeutic agent may be delivered to the treatment site
before an interventional procedure, during, after an interventional
procedure, or combinations thereof. [0109] e. A therapeutic agent may be
delivered to the treatment site concurrently with a blood flow, with a
partial blood flow or with no blood flow using blood flow protection
devices.

[0110] The therapeutic agent may be made available to the treatment site
at amounts which may be sustainable, intermittent, or continuous; at one
or more phases; and/or rates of delivery.

[0111] In one aspect of the invention, improved ultrasound ultrasound
delivery catheters are provided that incorporate means for infusing
liquid medicaments (e.g., drugs or therapeutic agents) concurrently or in
conjunction with the delivery of ultrasonic energy. The delivery of the
ultrasonic energy through the catheter concurrently with the infusion of
therapeutic agents aids in rapidly dispersing, disseminating,
distributing, or atomizing the medicament. Infusion of at least some
types of liquid medicaments concurrently with the delivery of ultrasonic
energy may result in improved or enhanced activity of the medicament due
to: a) improved absorption or passage of the medicament into the target
tissue or matter and/or b) enhanced effectiveness of the medicament upon
the target tissue due to the concomitant action of the ultrasonic energy
on the target tissue or matter.

[0112] Delivery of a therapeutic agent may face a different release rate
during initial catheter activation compared to a normal and desirable
release. Usually, the initial release of the therapeutic agent is at a
higher rate/level than preferred due necessity to flesh the catheter
before activation. To avoid the therapeutic agent downstream losses,
distal or proximal protection or both may be used. Distal and/or proximal
protection devices are known in the art, as, for example, a simple,
low-pressure balloon catheter: when the balloon is expanded, it stops
blood flow. In such cases when distal and/or proximal protection devices
are used to prevent downstream flow of the therapeutic agent, a residual
portion of the therapeutic agent may be removed or retrieved outside the
body using conventional vacuum methods after exposure to the vessel wall
for about one second to one hour.

[0113] Another object of the present invention is to provide an ultrasound
apparatus to deliver ultrasound energy to the target tissue that utilizes
at least three principal modes: longitudinal waves, shear (transverse)
waves and surface (radial or elliptic) waves, among others including Lamb
waves, Love waves, Stoneley waves or Sezawa waves. In longitudinal waves,
the oscillation occurs in the longitudinal direction or the direction of
wave propagation. In shear waves, oscillation occurs transverse to the
direction of propagation. Transverse waves are relatively weak compare to
longitudinal waves and are known to not effectively propagate through
liquids. Surface waves are mechanical waves that propagate along the
interface between differing media. Surface waves travel the surface of a
solid material or liquid penetrating to a depth of one wavelength.
Surface waves combine both a longitudinal and transverse motion to create
an elliptic orbit motion. The major axis of the ellipse is perpendicular
to the direction of the propagation of the wave.

[0114] Methods and devices of the invention that have been described above
in general terms will now be described in further detail in the context
of FIGS. 1-15. Referring to FIGS. 1 and 2, one embodiment of an
ultrasound system 90 for delivering ultrasound and therapeutic agents for
treating and/or inhibiting stenosis and/or restenosis is shown. The
ultrasound system 90 includes an ultrasonic catheter device 100, which
has an elongate catheter body 101, having an inside lumen/space 111. The
catheter 100 comprises a proximal end 102 and a distal end 103, and an
ultrasound transmission member/wire 110 disposed in the lumen 111 (FIGS.
2B and 2C).

[0115] The ultrasound transmission member or wire 110 is attached to the
tip 104 on the distal end of the catheter 100 and to a connector
assembly/knob 105 at the proximal end of the catheter 100. The ultrasound
catheter 100 is operatively coupled, by way of a sonic connector 112
(FIG. 2A) located within the proximal connector assembly/knob 105, to an
ultrasound transducer 120. The ultrasound transducer 120 is connected to
a signal generator 140. The signal generator 140 may be provided with a
foot actuated on-off switch 141.

[0116] When the on-off switch 141 is turned on, the signal generator 140
sends an electrical signal via line 142 to the ultrasound transducer 120,
which converts the electrical signal to vibrational energy. Such
vibrational energy subsequently passes through the sonic connector 120
(inside the connector assembly/knob 105) to the catheter device 100, and
is delivered via the ultrasound transmission member 110 (FIGS. 2B and 2C)
to the distal tip 104. A guidewire 150 may be used in conjunction with
the catheter device 100 having the entry at the distal tip 104 and exit
port 151.

[0117] The generator 140 includes a device operable to generate various
electrical signal wave forms such as continuous, pulse or combinations of
both within frequencies range between 1 kHz and 10 MHz, and produces
power of up to 20 watts at the distal end of the catheter tip 104. Thus,
ultrasound energy may be provided in continuous mode, pulse mode, or any
combination thereof. Also, to minimize stress on the ultrasound
transmission member 110 during, activation, the operational frequency of
the current and/or the voltage produced by the ultrasound generator 140
may be modulated. Movement of the distal end of the drug delivery
catheter may be provided in several forms vibrational energy such as
longitudinal fashion, transverse fashion, radial (surface waves) fashion
or a combination of all three forms. Propagation of vibrational energy
from the vibrational energy source through the ultrasound catheter may be
provided in the similar way. An injection pump 160 or IV bag (not shown)
maybe connected by way of an infusion tube 161 to an infusion port or
sidearm 109 of the Y-connector 108. The injection pump 160 is used to
infuse coolant fluid (e.g., 0.9% NaCl solution) from the irrigation fluid
container 162 into the inner lumen 111 of the catheter 100. Such flow of
coolant fluid serves to prevent overheating of the catheter 100 during
vibrational energy delivery. Due to the desirability of infusing coolant
fluid into the catheter body 101, at least one fluid outflow channel 107
is located either in the distal tip 104 or in the catheter body 101 at
the distal end 103 to permit the coolant fluid to flow out of the distal
end of the catheter 100. Such flow of the coolant fluid through the
catheter body 100 serves to bathe the outer surface of the ultrasound
transmission member. The temperature and/or flow rate of coolant fluid
may be adjusted to provide adequate cooling and/or other temperature
control of the ultrasound transmission member. Such an irrigation
procedure may also be performed by conventional syringes and other
devices suitable for liquid injection.

[0118] In addition to the foregoing, the injection pump 160 may be
activated by the foot actuated on-off switch 141 at the same time as the
generator 140. Therapeutic agents may be delivered together with an
irrigation fluid into the catheter device 100 using the injection pump
160 and carried to the distal end 103 of the catheter 100. Therapeutic
agents may be mixed, dissolved, synthesized or emulsified with other
drugs solvents, liquids, or irrigation fluid and delivered to human body
using injection pump 160. When injected into the irrigation lumen, such
therapeutic agents combined with irrigation liquid flow through the
catheter inner lumen 111 and cool the ultrasound transmission member 110
of the ultrasound catheter 100 while activated. When a therapeutic agent
leaves the ultrasound catheter 100 at distal end 103, it will contact and
at least partially be absorbed by the blood vessel wall. Optionally,
therapeutic agent may be infused separately into the catheter 100 through
the other port 180 of the Y-connector 108, thus, delivering a therapeutic
agent independently through a separate lumen (not shown) or not as a
mixture with irrigation fluid. A therapeutic agent can be delivered into
the catheter 100 through the port 180 using syringe 181 or other
injection device concurrently with irrigation fluid. Optionally, a
therapeutic agent may be delivered to the distal end 103 of the catheter
100 independently of the catheter 100. For example, in one embodiment, a
separate lumen for a therapeutic agent inside the catheter body 101 may
be provided (not shown). Alternatively, an additional sheath 602 around
the catheter 100 as shown in FIG. 6 may be employed. In another
alternative embodiment, a direct injection of a therapeutic drug from a
guiding catheter or introducer sheath into the treatment area may be
utilized.

[0119] Although the ultrasound catheter 100 in FIG. 1 is illustrated as a
"monorail" catheter device, in alternative embodiments the catheter 100
may be provided as an "over-the-wire" or guidewire-free device, as are
well known in the art.

[0120] Referring now to FIGS. 2A, 2B, and 2C, more detailed views of
embodiments of the ultrasound catheter 100. In this embodiment, the
ultrasound catheter 100 includes an elongated flexible catheter body 1.01
having an elongated ultrasound transmission member 110 that extends
longitudinally through the inner lumen of the catheter body 111. A sonic
connector 112 is positioned on the proximal end of the catheter 100 and
attached to the ultrasound transmission member 110. The sonic connector
112 provides the attachment of the ultrasound catheter, more specifically
the ultrasound transmission wire to an external ultrasound energy source.
The sonic connector 112 is housed inside the knob 105 and is attached to
the ultrasound transducer 120 when performing a procedure. While the knob
105 serves as a secondary interface between the ultrasound catheter 100
and the ultrasound transducer 120, the sonic connector 112 is securely
attached to the transducer horn and transfers ultrasound vibrations from
the transducer 120 to the ultrasound transmission member 110. The
ultrasound transmission member 110 carries vibrational energy to the tip
104 located at the distal end of the catheter 100.

[0121] In an embodiment wherein the ultrasound catheter 100 is constructed
to operate with a guidewire, an inner guidewire tube 113 may be extended
within the inner lumen 111 of the catheter body 101 and attached to the
tip 104 on the distal end. The other end of the guidewire tube 113 may be
attached along the length of the catheter body 101. The guidewire exit
port 151 may be positioned closer to the end of the catheter body or
closer to the proximal end of the catheter body 100. The catheter 100
shown may be deployed with the use of the guidewire as either a
"monorail" or an over-the-wire arrangement.

[0122] The catheter body 101 maybe formed of any suitable material,
including flexible polymeric material such as nylon (Pebax®) as
manufactured by Atochimie (Cour be Voie, Hants Ve-Sine, France). The
flexible catheter body 101 is generally in the form of an elongate tube
having one or more lumens extending longitudinally therethrough.

[0123] The distal tip 104 is a substantially rigid member firmly affixed
to the transmission member 110 and optionally affixed to the catheter
body 101. The distal tip 104 has a generally rounded configuration and
may be formed of any suitable rigid metal or plastic material, preferably
radio-dense material so as to be easily discernible by radiographic
means.

[0124] The tip 104 is attached to the ultrasound transmission member 110
by welding, adhesive, soldering, crimping, or by any other appropriate
means. A firm affixation of the ultrasound transmission member 110 to the
distal tip 104 and sonic connector 112 is required for vibrational energy
transmission from the transducer 120 to the tip 104. As a result, the
distal tip 104, and the distal end 103 of the catheter body 101 is caused
to undergo vibrations.

[0125] The ultrasound transmission member 110 may be formed of any
material capable of effectively transmitting the ultrasonic energy, such
as, by way of example, metal, fiber optics, polymers, and/or composites
thereof. In some embodiments, a portion or the entirety of the ultrasound
transmission member 110 may be formed of one or more shape memory or
super elastic alloys. Examples of super-elastic metal alloys that are
appropriate to form the ultrasound transmission member 30 of the present
invention are described in detail in U.S. Pat. Nos. 4,665,906 (Jervis),
4,565,589 (Harrison), U.S. Pat. No. 4,505,767 (Quin), and U.S. Pat. No.
4,337,090 (Harrison). The disclosures of U.S. Pats. U.S. Pat. No.
4,665,906; U.S. Pat. No. 4,565,589; U.S. Pat. No. 4,505,767; and U.S.
Pat. No. 4,337,090 are expressly incorporated herein by reference as they
describe the compositions, properties, chemistries, and behavior of
specific metal alloys which are super-elastic within the temperature
range at which the ultrasound transmission member 110 of the present
invention operates, any and all of which super-elastic metal alloys may
be usable to form the super-elastic ultrasound transmission member 110.

[0126] A therapeutic agent is infused through the inlet port 109 of the
Y-connector 105 and the lumen 111 of the catheter body 101 when delivered
as mixture with an irrigation fluid (FIG. 1). If a therapeutic agent is
infused separately, the port 180 may be used. The outlets ports for the
therapeutic agent from the catheter 100 either when drug is delivered as
a mixture with the irrigation fluid or separately through the port 180
are located at the distal end 103 of the catheter 100. In some
embodiments, outlet ports 106 are located in the distal tip 104 only, and
are positioned to deliver a therapeutic agent (and irrigation fluid) in a
radial manner, around the distal tip. In another embodiment, outlet ports
107 maybe located in the wall of the catheter body 101 at its distal
portion 103.

[0127] Various other arrangements and positioning of the respective
drug/irrigation outlet ports 106 and 107 may be utilized in other
embodiments of the invention. The size and number of these outlet ports
may vary depending on the specific intended function of the catheter 100,
the volume or viscosity of the therapeutic drug intended to be infused,
and/or the relative size of the therapeutic area to which the drug is to
be applied. In other embodiments, outlet ports may be located in both
mentioned locations as shown in FIG. 2C. In some embodiments, outlet
ports are located in such order that irrigation liquid and therapeutic
drug are distributed evenly around the distal end 103, and in such
fashion that the same volume and pressure at each outlet port are
achieved to assure uniform distribution and application of a therapeutic
drug to the vessel wall.

[0128] With reference now to FIGS. 3A, 3B, and 3C, in some embodiments of
the invention, a therapeutic agent may be delivered to a vascular
stenosis site as a stand-alone treatment (i.e., without contemporaneous
angioplasty, venoplasty or stenting). Such a separate therapeutic agent
therapy may be used, for example, when the vascular stenosis has not
closed a vessel by more than 50% and there is no significant blood flow
disturbance effect in supplying blood to surrounding areas and organs.
Alternatively, to improve the final result, in some embodiments a
conventional angioplasty or venoplasty procedure such as balloon
angioplasty or venoplasty, stent, atherectomy, laser treatment or
combinations of these therapies may be used before or after a therapeutic
agent delivery procedure.

[0129] In FIG. 3A, the distal end 103 of the ultrasound catheter 100 is
introduced inside the vessel 300 over the guidewire 150 and positioned
within the stenosis or treatment area 301. The distal tip 104 of the
ultrasound catheter 100 has a series of radial holes 106 that serve as
outlet ports for irrigation fluid and therapeutic drug. When ultrasound
energy is delivered to the catheter 100, the distal tip 104 vibrates
causing the irrigation fluid and therapeutic drug passing out of the
catheter 100 to mix together, to be pulverized into droplets 302, and to
disperse outward, all of these effects increasing permeation of the drug
into the vessel wall. Also, the vibrating tip 104 of the ultrasound
catheter 100 may cause local vasodilatation or sonophoresis around the
surrounding tissue, thereby creating micro indentation in the treatment
area 301 due to cavitation, increasing its permeability, and allowing the
applied drug to penetrate better into the vessel wall. Delivery of
ultrasound energy from the tip 104 to the treatment area 302 promotes
intracellular activation of cells by irradiating tissue with ultrasound
energy to cause an improved passage of a therapeutic drug into the
treatment area 301.

[0130] To cover a larger area of treatment, the catheter tip 104 may be
repositioned within the vessel 300, either longitudinally, radially, or
by both orientations as required. The catheter 100 may also be rotated
within the vessel 300 if desired. The embodiment of FIG. 3B differs from
that of FIG. 3A in that therapeutic agent outlet ports 107 are located in
the wall of the catheter body 101 instead of at the tip 104 as shown in
FIG. 3A. The embodiment in FIG. 3C shows the provision of both types of
outlet ports 106, 107 as illustrated in FIG. 3A and FIG. 3B combined.
During ultrasound energy delivery, outflow mixture of the irrigation
fluid and therapeutic drug from ports 106 and 107 is being dispersed,
pulverized into droplets 302 and delivered to the treatment site 301.

[0131] Alternative embodiments of devices and methods of the invention
(not shown) include applying or coating the therapeutic agent to the
exterior of a balloon that is attached to the distal end of the
ultrasound catheter. Inflation of the balloon enables approximation of
the therapeutic drug to the vessel wall and at least partial stasis of
the blood flow through the blood vessel. In combination with balloon
inflation, ultrasound energy at the catheter tip is activated which may
cause local vasodilatation or sonophoresis around the surrounding tissue
to enable greater penetration of the drug delivery. Also, ultrasound
energy in combination with the fluid elements on the inside lining of the
blood vessel may enable transformation of the drug coating from the
balloon to the blood vessel.

[0132] Other alternative embodiments of devices and methods for the
present invention (not shown) include the use of a porous balloon
attached to the end of the ultrasound catheter. In these embodiments, the
balloon is inflated with the therapeutic agent inside, and the balloon
weeps the therapeutic drug as the pressure inside the balloon increases.
While the drug weeps through the balloon materials or through small holes
in the balloon, ultrasound energy is activated to enable local
vasodilatation or sonophoresis around the surrounding tissue to aid in
increased drug penetration into the targeted blood vessel.

[0133] Still other alternatives embodiments of devices and methods the
invention (not shown) include ultrasound-assisted delivery of therapeutic
agents that are delivered either, before, during or after the
endovascular recanalization step, to improve arterial stenosis or
restenosis. Types of stenosis that could be treated by this technology
and method include minor atherosclerotic disease to chronic total
occlusions (CTO). Recanalization of the vessel can be achieved by a
multitude of ablation technologies (e.g. ultrasound,
atherectomy,radiofrequency) or mechanical means (e.g., balloon). In one
specific example, the same ultrasound device may be used both to ablate
the CTO and to assist delivery of the therapeutic agent to the vessel
wall while recanalizing the CTO site. Also, as another alternative, after
the initial recanalization and delivery of therapeutic agent to the
target tissue, a follow up therapy such as balloon angioplasty
venoplasty, stent or other may be employed.

[0134] Yet further alternative embodiments of devices and methods the
invention (not shown) include the use of a mesh device that is made of
metal, polymer, or a combination of such materials that is attached to
the end of the ultrasound catheter. Such mesh devices may be used in a
similar way as the balloon devices described above, either coated or not
coated with a therapeutic agent.

[0135] In most cases, ultrasound enhanced drug delivery to treat stenosis
and restenosis may be applied to existing atherosclerotic disease.
However, it may also be used in some embodiments as a preventive measure
in areas that are vulnerable to atherosclerotic disease or stenosis
generally, such as an area referred to as a "vulnerable plaque".

[0136] Referring now to FIGS. 4A and 4B, one embodiment of the method of
the invention may include first performing a conventional angioplasty or
venoplasty (FIG. 4A) and then delivering a therapeutic agent (FIG. 4B).
In this embodiment, as shown in FIG. 4A, a balloon catheter 400 having a
balloon 401 is introduced over the wire 150 inside the vessel 400 to the
treatment area 402. FIG. 4B shows a previously diseased area 402
compressed by the balloon 401 inflation. The ultrasound catheter 100 is
introduced over the same guidewire 150 to a newly reconfigured disease
area 410 (post balloon angioplasty or venoplasty). A therapeutic agent is
delivered to the distal end of the ultrasound catheter 100 having outlet
ports 106 located in the tip 104, and outlet port 107 located in the wall
of the catheter body 101. The mode of operation and action is the same as
that described in FIGS. 3A, 3B, and 3C.

[0137] In other embodiments of the invention, as shown in. FIG. 5. a
stenosis treatment system 500 may include an ultrasound/drug delivery
catheter 520 coupled with a distal flow protection device 501 to prevent
downstream flow of blood and therapeutic drug. In this embodiment, a
low-pressure compliant balloon 502 is mounted on the distal end of the
protection device 501, in this case a small, guidewire size device. One
current example of such device is the PercuSurge Guardwire®
(Medtronic/PercuSurge, Minneapolis, Minn.). The balloon 502 is inflated
accordingly and the ultrasound energy enhanced drug delivery is performed
as described in FIGS. 3A-3C. The balloon 502 of the protection device 501
may be fully inflated as shown in FIG. 5, so that no therapeutic drug is
delivered beyond the treatment site 510. If desired, the balloon 502 may
be deflated and inflated to allow ultrasound enhanced drug delivery to a
whole length of the treatment area 510. Such blood flow protection
feature may be achieved also by installing a similar balloon onboard the
ultrasound catheter 100, proximal to therapeutic agent outlets. An
example of such a device is described by Passafaro et al. (U.S. Pat. No.
5,324,255). A balloon feature described by Passafaro et. al., onboard the
ultrasound device may serve two functions, as an angioplasty or
venoplasty device and as a blood flow protection device, as desired.
Also, blood flow protection at the treatment area may be achieved using a
proximal protection device such as guiding catheter with a balloon
onboard. These devices are known in the art and will not be described
further.

[0138] An alternative embodiment (not shown) to prevent downstream flow of
blood and therapeutic drug is inflating a balloon or a mesh device
proximal to the ultrasound drug delivery location. Such a balloon or mesh
device can be integrated with the ultrasound/drug delivery or be a
separate catheter device. Use of a balloon or mesh elements in any of the
embodiments described in this application can be used to prevent
downstream delivery of the drug and to enable faster delivery, or the
delivery of greater amounts, of drug to the targeted tissue.

[0139] An alternative embodiment (not shown) to prevent downstream flow of
blood and therapeutic drug migration when a flow protection device is
used may include retrieving residual mixture of drug/blood/solvent
outside the body to minimize any systemic toxic effect.

[0140] FIG. 6 shows another embodiment of the present invention. The
ultrasound catheter 100 is delivered to the diseased area 601 inside the
vessel 600 over the wire 150. An additional single lumen sheath 602 is
positioned over the ultrasound catheter 100. A therapeutic agent is
delivered from an independent source and separately from the irrigation
system of the catheter 100. The additional sheath 602 is a single lumen
catheter having an inner lumen 603 extending longitudinally, and is
positioned over the ultrasound catheter 100. A therapeutic agent is
delivered through the lumen 603 and exits the sheath 602 at the distal
end 604 thereof which is positioned in the vicinity of the distal end 103
of the ultrasound catheter 100. Activation of the ultrasound catheter 100
causes the catheter distal tip and the immediate area of the catheter 100
distal portion 103 to vibrate. Vibrations of the distal end 103 causes a
therapeutic drug delivered from the distal end of the sheath 602 to be
pulverized into droplets 302 and delivered to the treatment site 601.
Also, a vibrating tip 104 of the ultrasound catheter 100 may continue to
induce local vasodilatation around the surrounding tissue 602, further
increasing its permeability, so that the applied drug penetrates into the
vessel wall. Due to the nature of therapeutic drug supply from the sheath
602, a flow protection may be appropriate.

[0141] Any of the therapeutic agents detailed above may be introduced to a
treatment site using the methods and devices described herein, with or
without coolant fluid (e.g., 0.9% NaCl solution). Alternatively, or
additionally, in other embodiments, a therapeutic agent may be delivered
along with a contrast agent, such as an angiographic contrast agent, for
diagnostic purposes. Any suitable contrast agent may be used in
combination with a therapeutic agent of the present invention, delivered
together or separately, either with contrast agent diluted with the 0.9%
NaCl solution or at 100% concentration. Also, a therapeutic agent may be
delivered in solution with Carbamide [(NH2)2CO] into the artery
or vein to the treatment location.

[0142] An illustrative clinical example of an application of the invention
will now be provided, in which the described ultrasound enhanced delivery
of therapeutic agent is applied to the treatment of a patient with a
stenotic coronary artery or vein. Following the diagnosis of a chest pain
or angina in the patient, it is radiographically determined that the left
coronary artery or vein is significantly occluded and that blood flow to
the left side of hart is impaired. A coronary guide catheter is inserted
percutaneously into the patient's femoral artery or vein and such guide
catheter is advanced and engaged in the left coronary ostium. A guide
wire is advanced through the lumen of the guide catheter to a location
where the distal end of the guidewire is advance directly through or
immediately adjacent to the obstruction within the left coronary artery.
An ultrasound catheter 100, an embodiment of the present invention, as
shown in FIGS. 1-6, is advanced over the pre-positioned guide wire 150 by
inserting the exteriorized proximal end of the guide wire into the guide
wire passage formed in the distal tip 104 of the catheter 100. The
catheter 100 is advanced over the guide wire 150, such that the proximal
end of the guide wire 150 emerges out of guide wire exit port 151. The
ultrasound catheter 100 is advanced to the coronary obstruction to be
treated as shown in FIGS. 3A-3C. Thereafter, a container 162 of sterile
0.9% NaCl solution may be connected, by way of a standard solution
administration tube 161 to the coolant infusion side arm 109 and a slow
flow of saline solution is pumped or otherwise infused through sidearm
109, through the lumen 111 of the catheter body 101 and out of outlet
ports located at the tip 104 or the distal portion 107 of the catheter
body 101, as shown in FIG. 3B. An intravenous infusion pump 160 is then
used to provide such flow of coolant fluid through the catheter. The
proximal connector assembly 105 of the catheter 100 is then connected to
the ultrasound transducer 120 via sonic connector 112, and the ultrasound
transducer 120 is correspondingly connected to the signal generator 140
so that, when desired, ultrasonic energy may be passed through the
catheter 100. A therapeutic agent is mixed with a sterile 0.9% NaCl
coolant solution and delivered from the bottle 162 and tube 161 to the
coolant infusion port 109 of the catheter 100. Alternatively, a
therapeutic agent may be injected through the other port 180 and syringe
181, separately from the coolant fluid.

[0143] To initiate delivery of a therapeutic agent, the flow of coolant
infusion mixed with a therapeutic agent is delivered from the bottle 162
to the infusion port 109 and maintained at an appropriate flow rate while
the signal generator 140 is activated by compression of on/off foot pedal
141. When actuated, electrical signals from the signal generator 140 pass
through cable 142 to ultrasound transducer 120. Ultrasound transducer 120
converts the electrical signals into ultrasonic vibrational energy and
the ultrasonic energy is passed through the ultrasound transmission
member of the catheter 100 to the distal tip 104 and its distal portion
103. The distal portion 103 of the catheter 100 may be moved,
repositioned back and forth by the operator to deliver therapeutic agent
to the entire treatment site thereby treating the stenosis of the
occluded left coronary artery. After the ultrasonic enhanced delivery of
a therapeutic agent has been completed, and after the desired dose of
drug has been delivered through the catheter 100 to the treatment site
301, the infusion of irrigation fluid and therapeutic agent is ceased and
the signal generator 140 de-actuated. Thereafter, the ultrasound catheter
100 and guidewire 150 are extracted from the coronary artery, into the
guide catheter and outside the body, and then, the guide catheter is
retracted and removed from the body. The ultrasound enhanced delivery of
a therapeutic agent is considered as the first line therapy

[0144] Referring now to FIGS. 7A and 7B, another method according to the
present invention may include first performing a conventional angioplasty
or venoplasty, which is represented by a reconfigured diseased area 701
(post balloon angioplasty or venoplasty), then delivering only a
therapeutic ultrasound energy using the ultrasound catheter 100 as shown
in FIG. 7A. The ultrasound catheter 100 is capable of delivering
therapeutic agent, but in this embodiment emits only ultrasound energy to
the vessel wall around diseased area 701 in the form of sonic waves 702.
Ultrasound energy application may be provided by any other suitable
ultrasound catheter. The ultrasound catheter 100 can be repositioned
within the vessel back and forth over the guidewire 150 as shown by the
double arrow 703 to cover a whole area of treatment and to create
desirable sonoporation and vasodilatation effects for a better drug
permeability into the vessel wall. After delivery of ultrasound energy,
the ultrasound catheter is removed and a conventional drug delivery
catheter 710 as shown in FIG. 7B is introduced over the guidewire 150 to
a newly treated area after the initial ultrasound exposure to the area
701. A therapeutic agent is delivered from an independent source, such as
through drug outlets 715 at the distal end of a drug delivery catheter
710. The drug delivery outlets 715 are positioned in the vicinity of the
newly modified treatment area 720, and the therapeutic agent 716 is
delivered to the vessel wall. The drug delivery catheter maybe reposition
back and forth in the vessel as shown by the double arrow 704 represent
the entire treatment area 720, and until the application of the
therapeutic agent is completed. Due to the nature of certain therapeutic
drugs, a flow protection may be appropriate (not shown) for such drugs.

[0145] Also, all above described embodiments related to the application of
a therapeutic agent to the vessel wall may be carried out in conjunction
with emitting ultrasound energy to the vessel wall from an external
ultrasound device in a transcutaneous fashion as shown in FIG. 8A and 8B.
FIG. 8A shows a human lower extremity (e.g., leg) 805 with an external
ultrasound transducer 806 positioned on the skin 807 around the treatment
area. The external ultrasound energy source can be a transducer 806
connected via a cable 808 to an ultrasound generator 809. The ultrasound
generator 809 converts line power into a high frequency current that is
delivered to the transducer 806. The transducer 806 comprises
piezoelectric crystals that convert high frequency current into
ultrasonic energy that is delivered into the leg 805 through the skin
807. The generator 809 includes a device operable to generate various
electrical signal wave forms such as continuous, pulse or combinations of
both, within a frequency range between 1 kHz and 10 MHz, and can produce
a power output of up to 100 watts at transducer 806. The ultrasound
energy may be provided in continuous mode, pulse mode, or any combination
thereof. Also, to improve efficacy and minimize stress as well as reduce
a potential thermal damage to the skin 807 between the transducer 806 and
the surrounding skin area during ultrasound energy activation, the
operational frequency, as well as current/voltage produced by the
ultrasound generator 809, as well as timing/pulsing may be modulated. In
addition, ultrasound transmission gel 811 (e.g., such as that
manufactured by Graham-Field, Bay Shore, N.Y.) may be used between the
transducer 806 and the skin 807 to reduce skin burns. A non-limiting
example of a suitable ultrasound device includes the TIMI3 Transcutaneous
System (Santa Clara, Calif.). As shown in FIG. 8B, the transducer 806
produces ultrasound waves 802 that propagate through the skin 807 and leg
tissue 803 to the treatment area 801 of the vessel 800. The treatment
area 801 may often be a reconfigured diseased area after initial
angioplasty or venoplasty. The drug delivery catheter 810 is positioned
over the guidewire 150 inside the vessel 800 around the treatment area
801. A therapeutic agent 816 is delivered through the distal outlet ports
815 of the drug delivery catheter 810 in a radial fashion towards the
treatment area 801. The therapeutic agent 816 can be delivered before,
during and after ultrasound energy delivery from the transducer 806. The
vibrating transducer 806 produces sound waves 802 that penetrate through
the leg skin 807 and the tissue 803 to the treatment area 801, and
induces local vasodilatation and sonoporation within the surrounding
tissue, further increasing its permeability, so that the applied drug
penetrates into the vessel wall.

[0146] FIG. 9 illustrates another method to deliver ultrasound energy to
the treatment area to enhance vessel permeability according to the
present invention. An ultrasound catheter 902 has a distal ultrasound
flexible member or probe 903 with a distal rounded, non-traumatic tip
904. Ultrasound energy produced by the generator 140 and the transducer
120 as shown in FIG. 1 is delivered through the ultrasound transmission
member 110 as shown in FIGS. 21B and 2C. The transmission member 110 has
a flexible distal member 903 that is located outside the ultrasound
catheter 902. The ultrasound catheter 902 and distal flexible member 903
are positioned within the treatment (diseased) area 901 inside the vessel
900. The entire length of the flexible member 903 is exposed to the
diseased area 901 inside the vessel 900. There is a distal marker 905
located on the end of the catheter 902 which provides positioning and
visualization under fluoroscopy for the catheter 902 and flexible member
903.

[0147] As used herein, three modes of propagated ultrasound energy
(longitudinal waves 907, transverse waves 909 and surface waves 908) may
be delivered along the flexible member 903. While it is difficult to show
schematically all these three sound waves simultaneously, FIG. 9 provides
representative wave illustrations serve for explanation purpose only and
which do not limit claims made herein.

[0148] The entire length of the flexible member 903 serves as an active
member that delivers ultrasound energy to the adjacent diseases area 901.
The injection pump 160 is used to infuse coolant fluid (e.g., 0.9% NaCl
solution) from the irrigation fluid container 162 (as shown in FIG. 1)
into the inner lumen 906 of the catheter 902. Such flow of
coolant/irrigation fluid serves to prevent overheating of the ultrasound
transmission member 110 and flexible member 903 during ultrasound energy
delivery. In addition, once the irrigation fluid leaves the inner lumen
906 of the catheter 905, it works as a medium to propagate longitudinal
waves 907, surface waves 908 and transverse waves 909 toward the adjacent
tissue 901.

[0149] The flexible member 903 can be made from any metal suitable to
propagate ultrasound energy, and preferably has a circular shape having a
diameter anywhere between 0.1 mm to 2 mm and a length that can vary
anywhere between 1 mm and 500 mm. The operational frequency for the
flexible member can be between 1 KHz-10 MHz. While the time of ultrasound
energy exposure depends on vessel size and the severity of the disease,
the exposure time within the treated area can be anywhere between 1
second to 60 minutes. Ultrasound power delivered to the vessel wall
should not exceed 20 Watts to avoid tissue damage.

[0150] FIG. 10 illustrates another catheter device according to the
present invention. The catheter device comprises an ultrasound
transmission member 1000 having a distal tip 1001, a catheter body 1002
having a radiopaque marker 1003 and an attached guidewire lumen 1004
having a proximal exit port 1005. Connected to the proximal end of the
catheter body 1002 are a proximal connector 1006 having three ports 1007,
1008 and 1009, and a proximal knob 1010 having a distal portion 1011 and
proximal portion 1012. A guidewire 1013 is extended through. the
guidewire lumen 1004 and the guidewire exit port 1005. The guidewire 1013
and guidewire lumen 1004 are shown for reference only as the present
invention can be applied to both catheters that include and not include a
guidewire. The catheter body 1002 can be formed of any polymeric
material. The flexible catheter body 1002 is preferably an elongate tube
having one or more lumens extending longitudinally. The distal portion of
the three arm connector 1006 is connected to the proximal end of the
catheter body 1002 using techniques that are well-known in the catheter
art. Extending longitudinally through the lumen of the catheter body 1002
is the elongate ultrasound transmission member 1000. The proximal end
1100 of the ultrasound transmission member is extended through the
proximal end of the catheter body 1002, three arm connector 1006 and knob
1010 (as shown in FIG. 11), and the very proximal end of the ultrasound
transmission member 1100 is connected to the sonic connector 1101 (see
FIG. 11), which is removable connectable to the ultrasound transducer
(not shown). With such an arrangement, ultrasound energy passes from the
ultrasound transducer (not shown) through the sonic connector 1101, the
proximal end of the ultrasound transmission member 1000, and is delivered
to the distal tip 1001 of the ultrasound transmission member 1000 as
shown in FIG. 10. In one embodiment, the ultrasound transmission member
1000 may be formed of any material capable of effectively transmitting
the ultrasonic energy, and is preferably made from metals including but
not limited to titanium, aluminum and their alloys. Also, the ultrasound
transmission member 1000 can be formed with one or more materials which
exhibit super-elasticity. Examples of super-elastic metal alloys which
are usable to form the ultrasound transmission member of the present
invention are described in detail in U.S. Pat. No. 4,665,906 (Jervis);
U.S. Pat. No. 4,565,589 (Harrison); U.S. Pat. No. 4,505,767 (Quin); and
U.S. Pat. No. 4,337,090 (Harrison). The disclosures of U.S. Pat. Nos.
4,665,906; 4,565,589; 4,505,767; and 4,337,090 are expressly incorporated
herein by reference.

[0151] FIG. 11 illustrates the details of the proximal part of the
catheter device shown in FIG. 10. The distal portion 1011 of the knob
1010 has a partially threaded bore 1106. The port 1009 of the three arm
connector 1006 also has external threads 1107 and is attached to the
distal end 1011 of the catheter knob 1010 by threadably engaging the
threaded part 1107 of the port 1009 inside the bore 1106. An injection
pump, IV bag or syringe (not shown) can be connected to an infusion port
or sidearm 1007 of the three arm connector 1006. The injection pump, IV
bag or syringe can be used to infuse coolant fluid into and/or through
the lumen(s) of the catheter body 1002. Such flow of coolant fluid may be
utilized to prevent overheating of the ultrasound transmission member
1000. The port 1008 of the three arm connector 1006 may serve to deliver
therapeutic agents and to aspirate drugs after use if needed. It also can
be used to evacuate ablated plaque and blood clots. The very proximal end
of the ultrasound transmission member 1000 is attached to a sonic
connector 1101 which is configured to couple the proximal end of the
ultrasound transmission member 1000 to the horn of the ultrasound
transducer located inside the transducer housing 120 as shown in FIG. 1.
The proximal portion 1012 of the knob 1010 has a bore 1102 that
accommodates the sonic connector 1101. The sonic connector 1101 is
attached to the proximal end of the ultrasound transmission wire 1000 at
a joint 1109 using conventional methods such as crimping welding,
soldering or bonding. The sonic connector 1101 is positioned within the
bore 1102 with a pin 1103 placed through a hole 1104 in the proximal
portion 1012 of the knob 1010. The sonic connector 1101 has also a
through-hole 1105 which accommodates the pin 1103 and secures the sonic
connector 1101 inside the bore 1102 in a position aligned with the pin
1103. The sonic connector 1101 has some freedom to move around the pin
1103, so it can freely vibrate and propagate ultrasound energy to the
ultrasound transmission member 1000.

[0152] The ultrasound catheter shown in FIG. 10 is configured to propagate
ultrasound energy along the proximal end 1100 and produce surface waves
along the ultrasound transmission member 1000, and to further propagate
surface waves to the surrounding tissue directly or through irrigation
medium. To achieve the most optimal edifice, an absorber in the form of a
series of polymer o-rings 1108 or other means for mitigating transverse
motions, such as elastic element(s), can be positioned inside the
proximal bore 1106 of the knob 1011 and between the bottom of the bore
1106 and the distal end of the threaded part 1107 of the port 1009. A
preferable location for positioning the o-rings 1108 is outside the 1/4
δ (one-quarter wavelength) distance from the sonic connector 1101
as shown in the FIG. 11. Such a positioning will reduce transverse
motions while allowing longitudinal motions to propagate through the
ultrasound transmission member 1000. The number of o-rings 1108, or the
length and size of other elastic element(s), can be selected depending on
the intensity requirement of the surface waves along the ultrasound
transmission member 1000.

[0153] FIG. 12 shows an alternative structure of ultrasound transmission
member 1000. As described above, the distal ultrasound flexible member
1000 may undergo some undesired transverse motions that may cause the
ultrasound transmission member 1000 to break or experience failure. To
reduce such potential problems and related clinical challenges, a polymer
sheath 1200 can be positioned along the ultrasound transmission member
1000. Such a polymer sheath 1200 will allow ultrasound energy in form of
longitudinal waves to propagate to the distal tip 1001 of the ultrasound
transmission member 1000, while reducing transverse motions, thereby
generating surface waves along the ultrasound transmission member 1000
and further propagating these surface waves to the treatment area. In
addition, a polymer shell 1201 maybe added or fused around the distal tip
1001 for further tissue protection since a significant amount of heat may
be concentrated around this very distal area of the ultrasound
transmission member 1000 during ultrasound energy delivery. Polymer
materials that can be used for both the polymer sheath 1200 and the
polymer shell 1201 may include but is not limited to: PTFE, PTE,
polyurethane, polyamide, polyethylene or nylon. The polymer sheath 1200
may also be further extended proximally into the catheter body 1002. The
catheter body 1002 may be repositioned along the ultrasound transmission
member 1000 as required by the length of the treated area. The catheter
body 1002 includes a guidewire lumen 1004 that may be extended beyond the
distal end of the catheter body 1002. The guidewire exit port 1005 of the
guidewire lumen 1004 may be positioned at, or exit at, any desired
location along the catheter body 1002, including at the three-arm
connector 1106 and the knob 1010. The polymer material used for the
polymer shell 1201 and the polymer sheath 1200 can be mixed with a
radiopaque metallic powder to provide a better visibility of the
ultrasound transmission member 1000 and the distal tip 1001 under
fluoroscopy.

[0154] The ultrasound transmission member 1000 is configured to propagate
ultrasound energy in form of surface waves along the length of the
ultrasound transmission member 1000 that is exposed to the treatment
area, and located between the distal tip 1001 and the distal end of the
catheter 1002. The ultrasound transmission member 1000 can have at least
two regions of a different (decreasing) cross-sectional dimension (not
shown) to maintain a desired flexibility adjacent the distal end and
durability at the proximal end. The ultrasound transmission member 1000
extends longitudinally through the catheter 1002 and is connected to the
sonic connector 1101 as shown in FIG. 11. The ultrasound transmission
member 1000 may be tapered or narrowed, or have an increased
cross-sectional dimension so as to generally decrease the rigidity of the
ultrasound flexible member 1000 and to cause amplification of the
ultrasound energy transmitted to the distal portion of the ultrasound
transmission member 1000. The ultrasound transmission member 1000 may
have a plurality of intermediate tapered sections, progressively tapered
sections or a combination of both, having diameters that progressively
decrease from the area adjacent to the proximal region toward the distal
region. The ultrasound transmission member 1000 may also include a
continuous diameter or tapered structure, while the distal tip 1001 of
the flexible member may be larger, smaller, or have the same dimension as
the intermediate dimension of the ultrasound transmission member 1000,
The proximal end 1100 of the ultrasound transmission member 1000 as shown
in FIG. 11 may include any dimensional configuration required to optimize
ultrasound energy delivery to the ultrasound transmission member 1000.

[0155] FIG. 13 shows another alternative assembly of the ultrasound
transmission member 1000. As previously mentioned, the ultrasound
transmission member 1000 has a smaller cross sectional area along its
length than at the proximal end 1100. Also, the ultrasound transmission
member 1000 may include several narrowed regions to amplify energy
propagation. Such a structure is prone to stress concentration along the
ultrasound transmission member 1000 that may cause fracture or breakage
thereof Several measures may be taken to avoid such breakage, including
increasing the size of the ultrasound transmission member 1000, and using
energy pulsing or modulation to mitigate stress concentration, among
others. However, in case the ultrasound transmission member 1000 breaks,
parts of the ultrasound transmission member 1000 may be left behind in
the patient's body even when the ultrasound transmission member is
protected by the polymer sheath 1200 shown in FIG. 12. To address such a
possibility, an anchor member 1300 can be extended along the ultrasound
transmission member 1000 and attached at an attachment point 1301 to the
distal end 1001 of the ultrasound transmission member 1000. At the
proximal end, the anchor member 1300 may be attached to the ultrasound
transmission member 1000, the catheter 1002, the connector 1006, or the
proximal knob 1010 shown in FIGS. 10 and 11, or to the proximal end 1100
shown in FIG. 11. The anchor member 1300 will ensure that the ultrasound
transmission member 1000 can be entirely removed from the patient's body
in the case of breakage of the ultrasound transmission member 1000. The
anchor member 1300 may be made of metal, polymer or combination of both.
A radiopaque marker 1302 may be attached at the distal end of the
ultrasound transmission member 1000 if required to provide radiopacity at
the distal tip 1001. Attachments of the anchor member 1300 and radiopaque
marker 1302 can be done by conventional methods such as bonding, welding,
soldering, and crimping, among other. The distal tip 1001 may be further
covered with the polymer shell 1201 on the distal-most end to encapsulate
the radiopaque marker 1302, the distal portion of the anchor member 1300,
the attachment 1301, and the distal tip 1001 itself. In addition, the
polymer sheath 1200 may be extended along the ultrasound transmission
member 1000 and the anchor wire 1300 to mitigate transverse vibrations of
the ultrasound transmission member 1000. The construction of the catheter
1002 can be similar to one shown in FIG. 12, and include the radiopaque
marker 1003, and the guidewire lumen 1004 having proximal exit port 1005.

[0156] FIG. 14 shows another alternative structure of the ultrasound
transmission member 1000. An additional metallic tip 1400 can be attached
to the distal end 1001. Such a metallic tip may be helpful for crossing
tight stenosis and recanalization of Chronic Total Occlusions (CTO) which
often will have a well-organized and hardened composition that is
otherwise impossible to cross with conventional guidewires. The devices
in the embodiments described above may not always be suitable for such
applications because the plastic shell 1201 shown in FIGS. 12 and 13 may
be easily damaged while interfacing or crossing hard calcific plaque. A
radiopaque marker 1302 is also attached to the ultrasound transmission
member 1000. If the metallic tip 1400 is sufficiently radiopaque, the
radiopaque marker 1302 may not be necessary. The radiopaque marker 1302
may also be attached directly to the metallic tip 1400. An anchor member
1300 can also be attached to the tip 1001, and the polymer sheath 1200
and polymer shell (if necessary) may be attached in a similar fashion as
shown in FIGS. 12 and 13. The anchor member 1300 may also be attached to
the metallic tip 1400 at the attachment point 1301. The construction of
the catheter 1002 can also be similar to constructions shown in FIGS. 12
and 13, and can include the radiopaque marker 1003, and the guidewire
lumen 1004 having a proximal exit port 1005.

[0157] FIG. 15 illustrates the ultrasound transmission member 1000 shown
in FIG. 14, and in use with an additional catheter 1500 that is
positioned around the ultrasound transmission member 1000 and around the
catheter 1002. The additional catheter 1500 may serve an aspiration
purpose as illustrated with arrows 1501, either to remove ablated tissue,
therapeutic drug after use, blood clots or irrigation provided for
cooling of the ultrasound transmission member 1000 during ultrasound
energy delivery. The aspiration catheter 1500 may be positioned along the
distal end of the catheter 1002 and the ultrasound transmission member
1000 as needed to safely and effectively apply ultrasound energy to the
treated area while removing ablated tissue, therapeutic drug after use,
blood clots or irrigation material. A further alternative may be to
provide a single catheter with two lumens that can perform the same
functions as the catheter 1002 and the aspiration catheter 1500 (not
shown). The use of aspiration and ultrasound energy producing surface
waves at the same time may he particularly beneficial for removing blood
clots or thrombus from the patient's body. Examples of blood clot removal
includes but is not limited to Arterial and Venous Thrombolysis, Ischemic
Stroke, Deep Vein Thrombolysis (DVT), Pulmonary Embolism and any other
cavities in human body where blood clots needs to be removed.

[0158] Also the scope of the invention incorporates delivery of ultrasound
energy to the vessel wall before, during and after delivery of the
therapeutic agent. Drug delivery may be achieved using ultrasound drug
delivery catheters or any separate drug delivery device. Drug delivery
may also be achieved with intravenous drug delivery or with endovascular
methods using ultrasound drug delivery catheters or any separate drug
delivery device.

[0159] To achieve the required therapy effects, it is desirable to apply
ultrasound energy while most of the therapeutic drug is still present at
the treatment area. If the therapeutic drug is delivered first, it would
be advantageous to deliver ultrasound energy to the treatment area within
a short period of time after the drug has been applied. If ultrasound
energy is delivered first to the treatment area, the effect of ultrasound
to enhance drug permeability lasts from the time when energy is
delivered, and is usually no longer than 60 minutes after ultrasound
energy is exposed to the vessel wall.

[0160] Other alternative embodiments of devices and methods for the
present invention include delivery of the therapeutic drug intravenously
(IV) and enhancing permeability of the vessel wall via the delivery of
ultrasound energy to the treatment location. Ultrasound energy delivery
will induce local vasodilatation and sonoporation within the surrounding
tissue, further increasing drug uptake. Ultrasound energy may be emitted
to the treatment area using transcutaneous (from outside of the body) or
endovascular catheter methods. IV delivery of drug will cause a systemic
effect causing the entire blood system to carry the therapeutic drug. By
using a targeted ultrasound energy that is limited to a specific
treatment area, the applied drug penetrates into the vessel wall of the
treatment area more effectively. Emission of ultrasound energy and IV
delivery of the therapeutic drugs can be administered in a variety of
combinations: the therapeutic drug may be delivered intravenously either
before delivery of ultrasound energy to the treatment area, during
delivery of ultrasound energy or after delivery of ultrasound energy to
the treatment area. In addition, a treatment area may be exposed to any
other interventional procedure, including but not limited to: balloon
angioplasty or venoplasty, stent placement, atherectomy, laser procedure,
cryoplasty, other drug delivery and any combination of such procedures.
Any interventional procedure may take place either before, during or
after ultrasound/drug therapy. Further enhancement of the therapeutic
drug uptake in the treatment area may be achieved using distal, proximal
or dual flow protection or flow limitation devices such as compliant or
non-compliant balloon devices. Therapeutic drug(s) delivered through the
IV approach may be mixed with a conventional saline or any suitable
contrast medium.

[0161] Still other alternative embodiments of devices and methods of the
invention include delivery of ultrasound energy to a treatment area and
delivery of therapeutic agent(s) that are mixed with a suitable contrast
medium. The concept of using contrast media as a matrix for
antiproliferative drugs delivery can simply employ standard endovascular
angiography techniques. The contrast medium is chosen as the vehicle for
therapeutic drug delivery because it significantly enhances the
solubility of the drugs that are usually not easily solvent in
conventional saline. Examples of suitable contrast medium include but are
not limited to: Omnipaque 300, Amersham Health, N.J., USA; Ultravist-300,
Schering AG, Berlin, Germany and NIOPAM 300, Bracco UK Limited.
Ultrasound energy delivery will induce local vasodilatation and
sonoporation within the vessel wall, further increasing permeability of
the drug delivered with contrast medium. Ultrasound energy may be
delivered to the treatment area using transcutaneous methods (from
outside the body) or endovascular catheter methods. Delivery of
therapeutic drugs to the treatment area can be administered in a variety
of combinations: therapeutic drug may be delivered either before delivery
of ultrasound energy to the treatment area, during delivery of ultrasound
energy to the treatment area, or after delivery of ultrasound energy to
the treatment area. Therapeutic drug may be delivered by the ultrasound
catheter that is energized or not energized, by a separate drug delivery
catheter or through a conventional medium injection into a percutaneous
sheath. In addition, a treatment area may be exposed to any other
interventional procedure including but not limited to: balloon
angioplasty or venoplasty, stent placement, atherectomy, laser procedure,
ultrasound angioplasty or venoplasty, cryoplasty, other drug delivery and
any combination of such procedures. Any interventional procedure may take
place either before, during or after ultrasound/drug therapy. Further
enhancement of the therapeutic drug uptake in the treatment area may be
achieved using distal, proximal or dual flow protection or flow
limitation devices, such as for example, compliant or non-compliant
balloon devices.

[0162] Another embodiment of the present invention includes delivery of
ultrasound energy to a treatment area and delivery of therapeutic
agent(s) that are mixed with Carbamide. Carbamide is an organic compound
with the chemical formula (NH2)2CO. The molecule has two amine
(--NH2) groups joined by a carbonyl (C═O) functional group, and
is also known as urea. Urea serves an important role in the metabolism of
nitrogen-containing compounds by animals and is the main
nitrogen-containing substance in the urine of mammals. It is solid,
colourless, and odorless. It is highly soluble in water and non-toxic.
Dissolved in water, it is neither acidic nor alkaline. The body uses it
in many processes. most notably nitrogen excretion. Carbamide can be
synthesized in the lab without biological materials. It has been
hypothesized that Carbamide may be a good and effective solvent to dilute
Paclitaxel for use in anticancer and antistenosis therapy.

[0163] While the ultrasound delivery methods above describe transcutaneous
transducers that are located outside the body (for example, U.S. Pat. No.
6,398.772 (Bond et al.)) and endovascular transducers located on the
proximal end of the catheter (for example, U.S. Pat. No. 5,342,292 (Nita
et al.)), use of small endovascular transducers located at the distal end
of the catheter is also possible. Examples of such distal transducers are
illustrated in U.S. Pat. Nos. 5,728,062 (Brisken), 6,001,069 (Tachibana
et al.), 6,372,498 (Newman et al.), 6,387,116 (McKenzie et al.),
6,432,068 (Corl et al.), 6,484,052 (Visuri et al.), and 6,723,063 (Zhang
et al.), and these disclosures are hereby incorporated by this reference
as though set forth fully herein. The use of ultrasound energy to disrupt
clots and to enhance delivery of drugs to clots has been recently
proposed using a flexible probe, where the entire length of the probe
forms a cutting surface to ablate unwanted tissue in the transverse mode
of operation. Examples of such flexible probes are illustrated in U.S.
Pat. Nos. 6,551,337, 6,652,547 and 7,494,468, which solely relays
transverse motions of the flexible probe, and these disclosures are
hereby incorporated by this reference as though set forth fully herein.

[0164] The development of thrombosis as a result of vessel injury or
delayed endothelialization is a recognized risk of transcutaneous or
endovascular intervention with some therapeutic agents that may be used
to prevent restenosis. In such cases, administration of the appropriate
medication may be required.

[0165] Ultrasound energy delivered for stenosis and restenosis therapies
either in endovascular or transcutaneous fashion may be generated or
produced by longitudinal sound waves, transverse sound waves, radial
sound waves, or combination of these sound waves.

[0166] Although the invention has been described above with respect to
certain embodiments, it will be appreciated that various changes,
modifications, deletions and alterations may be made to such
above-described embodiments without departing from the spirit and scope
of the invention. Accordingly, it is intended that all such changes,
modifications, additions and deletions be incorporated into the scope of
the following claims. More specifically, description and examples have
been provided that relate to treatment of stenotic arterial sites and to
therapeutic agents that are appropriate for treating such sites. However,
the scope of the invention includes the application of these methods to
treating sites other than stenotic sites, and to facilitating the
intracellular delivery of any therapeutic agent appropriate for treating
the particular target site.

[0167] Some theoretical considerations have been provided as to the
mechanism by which these therapeutic methods are effective; these
considerations have been provided only for the purpose of conveying an
understanding of the invention, and have no relevance to or bearing on
claims made to this invention.